Ligand control of regioselectivity in palladium-catalyzed heteroannulation reactions of 1,3-Dienes

Olefin carbofunctionalization reactions are indispensable tools for constructing diverse, functionalized scaffolds from simple starting materials. However, achieving precise control over regioselectivity in intermolecular reactions remains a formidable challenge. Here, we demonstrate that using PAd2nBu as a ligand enables regioselective heteroannulation of o-bromoanilines with branched 1,3-dienes through ligand control. This approach provides regiodivergent access to 3-substituted indolines, showcasing excellent regioselectivity and reactivity across a range of functionalized substrates. To gain further insights into the origin of selectivity control, we employ a data-driven strategy, developing a linear regression model using calculated parameters for phosphorus ligands. This model identifies four key parameters governing regioselectivity in this transformation, paving the way for future methodology development. Additionally, density functional theory calculations elucidate key selectivity-determining transition structures along the reaction pathway, corroborating our experimental observations and establishing a solid foundation for future advancements in regioselective olefin difunctionalization reactions.

In this work Paradine and co-authors reported a new strategy to access 3-substituted indoline products from 1,3-dienes and ambiphilic molecules.It is exciting to see that the regioselectivity can be controlled by ligands, thus complementing the existing methods, which will usually lead to 2substituted indolines.They explained the origin of the regioselectivity in two ways: 1) They showed how the key parameters would affect the reaction; 2) They delivered DFT calculations to support the 2,1-migratory insertion mechanism.Given the fact that annulation between alkenes and ambiphiles remain popular during the past few decades, we could foresee that this work will inspire more regioselective annulations by ligand design.Although I have some concerns regarding the model they use and the scope of this work is somewhat limited, I lean to the acceptance of this work after the following concerns have been addressed.
(1) The modeling formula of Gibbs free energy in figure 2e is very confusing without explanation of each term.Could you please explain the meaning of each term in your model?For example, why you use a cross-term of electrophilicity parameter, etc.You should use linear regression to fit the coefficient of the variable only after you have a correct model.
(2) In this work the authors proposed a 2,1-carbopalladation pathway to explain the regioselectivity.This looks like a reasonable pathway based on their DFT calculation.However, I wonder if they have considered the Wacker-type aminopalladation pathway?See Inorg. Chem. 2007, 46, 6, 1910-1923 and Engle's recent annulation works.
(3) Figure 1a should be improved: They kept drawing the same product and saying "2,1-migratory insertion" again and again.They may want to save that space for more useful information.
(4) Do they have any explanations why the 3-substitution is required in the alkene?Have they ever tried any 3,4-disubstituted acyclic alkenes in the scope?
(5) Have they tried any other coupling partners such as O-/C-nucleophiles and anilines protected by other groups?Is it the yield or the selectivity issues?(6) On page 3 they said "twelve ligands shifted the selectivity towards the 3-substituted indoline".Based on figure 2c, there are only 6 ligands.
(7) 19F NMR should be added for the fluorine containing compounds.
(8) The 13C NMR for compound 1k (Page S4): where is the quartet CF3 peak?A careful proofreading of the SI is suggested.
Reviewer #2 (Remarks to the Author): Comments: This paper reported the ligand control strategy to synthesize 3-substituted indolines by Palladium-catalyzed heteroannulation reaction of o-bromoanilines and branched 1,3-dienes.This article combined the Kraken database, using multiple linear regression to show the origin of regioselectivity when different monophosphine ligands were used.We are very glad to see that the author's screening of phosphine ligand was rigorous and efficient, and this well-distributed sampling and experiment are very powerful for subsequent analysis.This model suggested that the weak noncovalent interactions should also be considered in the screening of phosphine ligands.According to the steric hindrance of ligands, different modes of active intermediates were proposed and verified by DFT calculations (three-coordinate palladium species for highly sterically-demanding monophosphine ligands and remaining monophosphine ligands).In the substrate scope, only 2substituted 1,3-dienes showed high yield and selectivity.The tolerance of other functional groups in this reaction cannot be demonstrated through this limited scope.In general, this paper is rigorous and novel in its interpretation of reaction selectivity, and we expect that this deep understanding of the mechanism will further expand the application of this reaction.But a major revision is needed 1.More groups should be added to the substrates to the reaction scope (such as carbonyl, ester, halogen, etc.).

Can the linear regression model predict a new monophosphine that could further expand the reaction scope?
We hope that this model can guide ligand screening or ligand designing.
3.The optimal reaction conditions of L1 were used as reaction conditions to test the reaction selectivity of other phosphines.But this could be wrong, especially in the case of weak noncovalent interactions emphasized in this paper.In this case, solvents may be an important influencing factor to that.Therefore, this should be tested.
Reviewer #3 (Remarks to the Author): The paper by Rodina et al. describes the development of a regioselective palladium-catalyzed annulative coupling reaction to form 3-substituted indolines guided by multivariate regression of numerical ligand descriptors against selectivity and density functional theory (DFT) calculations.The authors' findings provide an attractive method to obtain these harder-to-access indolines and provide insight on the factors that influence the success of the reaction.
The paper is well written and the figures are visually appealing and informative.The Supplementary Information (SI) appears thorough and the repeated measurement of yield for each reaction is commendable.
There are a few places where the writing could be refined, as indicated in the attached file.The revised manuscript has properly resolved my concerns.I feel that this work is ready to be accepted.
Reviewer #2 (Remarks to the Author): After reading the manuscript, I think that a major revision is still needed.1, the computed regiochemistry is too high compared to experimental results.The difference in activation free energies for the regio-determining transition states are too high (more than 7 kcal/mol) and cannot explain the experimental results.
2, Calculations should use real ligands, not the model ligands.
3, Analysis of the regiochemistry is very misleading.The linear aggregation analysis gave little information.Based on the results, steric effect is critical.Analysis of the key steric interaction is more straightforward for chemists to understand their experimental results.4, Global nucleophilicity is not a good parameter.Chemists are now using HOMO for nucleophilicity and LUMO for electrophilicity.See JOC, 2016,81, 5370.5, The authors named the last figure in the manuscript wrongly as Figure 3, which should be Figure 4 exactly.